Coronary artery disease remains the leading cause of death in the United States. Platelets play an important role in the pathogenesis of acute coronary syndrome (ACS), as platelet activation, aggregation and secretion are key components of arterial thrombus formation. Despite dual anti-platelet therapy for ACS and percutaneous coronary interventions (PCI), many patients sustain a high incidence (up to 20% at 3 years) of major adverse events such as death, myocardial infarction (MI) or stroke, and would benefit from new therapeutics that interfere with the other important pathways that regulate primary platelet activation. These findings underscore the fact that platelet activation requires multiple receptors and that receptor interactions play an important role in hemostasis while contributing to pathological thrombosis. Protease-activated receptor (PAR) 1 and 4 are activated by thrombin and trigger platelet activation/aggregation. Compared to heparin, the bleeding risk by targeting thrombin with bivalirudin is lower with similar reductions in cardiac events, but is accompanied by an increase in the rate of acute stent thrombosis. The two downstream thrombin receptors have distinct roles in platelet activation and each of these represents an independent therapeutic target. An oral drug targeting PAR1 is already in the clinic (not approved for acute indications due to bleeding risk), however there are no drugs yet approved for PAR4. Furthermore, PAR4 was recently shown to be a critical contributing factor for high thrombotic risk with potential differences in human platelet PAR4 reactivity that are found frequently in African-Americans (63%) as compared to Caucasians (19%). Individuals with `high' PAR4 reactivity include those that carry a single nucleotide polymorphism (SNP) in TM2. Therefore, PAR4 is an attractive anti-platelet target that may show extra benefit in preventing life-threatening arterial thrombosis in individuals with `high' PAR4 reactivity, while sparing the essential hemostatic effects of PAR1, collagen and thrombin. Oasis Pharmaceuticals has developed a potent fast-acting injectable PAR4 pepducin inhibitor, OA- 150, to prevent acute ischemic complications of arterial thrombosis in high-risk PCI patients that are not treatment candidates for a slow-onset oral PAR4 inhibitor. The goal of the proposed IND-enabling Phase I STTR studies is to generate an FDA-approved subcutaneous formulation (for clinical testing) for a PAR4 lipidated peptide inhibitor with: i) stability profile characterized from accelerated and long-term stability (>3 months); ii) a rapid onset (<30 min) of PAR4 platelet inhibition with a half-life that is optimal (~4-10 h) for acute prevention of ischemic events during PCI in ACS patients. Optimal subcutaneous formulation for the PAR4 pepducin will be used to demonstrate efficacy in rodent and primate models, favorable PK and rapid delivery to platelets in non-human primates and rodents. The ultimate goal of this STTR proposal is to rapidly advance the pre-clinical development of this highly promising parenteral PAR4 inhibitor into the therapeutic arena to potentially dramatically improve cardiovascular disease outcomes in high-risk patients.